Long-term neurobehavioral effects of ketamine exposure in adolescent mice

青少年小鼠暴露于氯胺酮的长期神经行为影响

• 批准号: 7356717
• 负责人: STEVEN J SIEGEL
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356717
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Age-Months; Apoptosis; Area; Astrocytes; Auditory; Auditory area; Award; Basic Science; Behavior; Biochemical; Brain; Brain Injuries; Brain region; Cell Death; Cells; Chronic; Class; Cognitive; Cognitive deficits; Coupled; Cues; DNA Nucleotidylexotransferase; DNTT gene; Data; Development; Drug abuse; Elements; Event-Related Potentials; Evoked Potentials; Exposure to; Glial Fibrillary Acidic Protein; Glutamates; Hippocampus (Brain); Histocytochemistry; Hour; ITGAM gene; Immunohistochemistry; Injection of therapeutic agent; Intoxication; Ketamine; Label; Lead; Literature; Measures; Mediating; Mental disorders; Methods; Microglia; Modeling; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nature; Necrosis; Neuroglia; Neuronal Plasticity; Neurons; Pattern; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Population; Principal Investigator; Receptor Activation; Receptor Mediated Signal Transduction; Receptor Signaling; Resistance; Role; Saline; Sensory; Sensory Process; Signal Transduction; Silver Staining; Surveys; Symptoms; Syndrome; Tyrosine Phosphorylation; Week; Work; aged; base; caspase-3; cellular pathology; cognitive function; college; conditioned fear; critical developmental period; density; dentate gyrus; design; discount; drug of abuse; high school; interest; ketamine abuse; mature animal; neurobehavioral; neurodevelopment; postsynaptic; receptor function; young adult

DESCRIPTION (provided by applicant): This is the second submission of a Phase II Cutting Edge Basic Research Award (CEBRA) that follows the Principal Investigator's Phase I application entitled, Evoked potentials and vulnerability to ketamine in mice (5-R21-DA-017082-02). All of the reviewers' concerns have been fully addressed in this revised application. Rationale: Experimentation with drugs of abuse is common among adolescents and young adults. Although the immediate consequences of intoxication are known, the ubiquitous nature of casual use leads many clinicians to discount mild drug abuse during high school and college as causal of later psychiatric symptoms and syndromes. Despite such assumptions, the lasting consequences of drugs that are emerging on campuses and in clubs across the nation, such as ketamine, are not known. During the Phase I portion of this study, the PI demonstrated persistent changes in Event Related Potentials (ERPs) following chronic ketamine exposure in adult mice. Preliminary data and previous literature also demonstrate that ketamine causes cellular pathology in brain. Questions that will be addressed: These findings lead to the following two overarching questions: 1) Does intermittent exposure to NMDA receptor antagonists during adolescence cause persistent physiological and cognitive deficits in adults? 2) Can adolescent ketamine abuse cause persistent alterations in cellular constituents and/or receptor signaling mechanisms in adults? Approach and Methods: Therefore, proposed studies will determine the duration of persistent ERP and cognitive deficits following ketamine exposure during adolescence in mice (Aim 1). Complementary studies will determine which cell classes are selectively altered by ketamine using stereological population estimates in adult animals following immunohistochemistry for cell-specific markers. Additionally, we will analyze measures of immediate cellular pathology directly following ketamine exposure during adolescence (Aim 2). Aim 3 will then utilize ex-vivo studies to determine the pattern of functional alterations of intracellular mechanisms of NMDA receptor mediated signal transduction among surviving cell populations following developmental exposure to ketamine. Significance: These three parallel Aims will address the degree of physiological, anatomical and biochemical functional neuroplasticity that exits following adolescent ketamine exposure. Therefore, completion of the proposed body of work will provide valuable evidence regarding the long-term, possibly irreversible, consequences of intermittent drug abuse during adolescence and early adulthood. Furthermore, these studies will address the potential roles of early drug abuse in later cognitive and psychiatric disorders throughout life.Although ketamine (Special K) abuse is common among adolescents, the consequences of this behavior are not known. To address this issue, we previously demonstrated that ketamine causes short-term changes in brain activity and signs of brain damage in adult mice. Proposed studies will determine the duration of abnormal brain function and the extent of brain damage following ketamine in adolescent mice to assess the potential for lasting, irreversible consequences of drug abuse during adolescence.

描述（由申请人提供）：这是II期最尖端基础研究奖（CEBRA）的第二次提交，该奖项遵循主要研究者的I期申请，其标题为小鼠（5-R21-DA-DA-DA-017082-02）的标题为诱发的潜力和脆弱性。在此修订的申请中，所有审阅者的关注都已充分解决。理由：在青少年和年轻人中，对滥用药物进行实验是常见的。尽管已知中毒的直接后果，但随意使用的无处不在的性质使许多临床医生在高中和大学期间折现了轻度的药物滥用，这是后来精神病症状和综合症的因果。尽管有这样的假设，但尚不清楚在校园和全国俱乐部中出现的毒品的持久后果。在本研究的第一阶段部分中，PI在成年小鼠的慢性氯胺酮暴露后显示事件相关电位（ERP）的持续变化。初步数据和以前的文献还表明，氯胺酮会导致大脑的细胞病理。将要解决的问题：这些发现导致以下两个总体问题：1）在青春期期间，间歇性接触NMDA受体拮抗剂是否会导致成人持续的生理和认知缺陷？ 2）青少年氯胺酮滥用会导致成人细胞成分和/或受体信号传导机制的持续改变吗？方法和方法：因此，拟议的研究将确定青春期氯胺酮暴露后小鼠的持续性ERP和认知缺陷的持续时间（AIM 1）。补充研究将使用氯胺酮使用成年动物的立体种群估计来确定哪些细胞类别在免疫组织化学特异性标记后选择性改变。此外，我们将分析青春期氯胺酮暴露后直接直接的细胞病理的测量方法（AIM 2）。然后，AIM 3将利用外病毒研究来确定NMDA受体介导的信号转导的功能改变的模式，因为在氯胺酮发育后，存活的细胞群体中，氯胺酮介导的信号转导模式。意义：这三个平行目的将解决青少年氯胺酮暴露后退出的生理，解剖和生化功能性神经可塑性的程度。因此，拟议的工作体系的完成将提供有关青春期和成年初期毒品滥用的长期（可能是不可逆的）后果的宝贵证据。此外，这些研究将解决早期药物滥用在后来的认知和精神疾病中的潜在作用。尽管氯胺酮（特殊K）滥用在青少年中很常见，但这种行为的后果尚不清楚。为了解决这个问题，我们先前证明氯胺酮会导致大脑活动的短期变化和成年小鼠脑损伤的迹象。拟议的研究将确定青少年小鼠中氯胺酮异常的脑功能和脑损伤程度，以评估青春期药物滥用的持久，不可逆转的后果的可能性。